Intramolecular C-H amination reactions

Fig. 80 (Porphyrin)cobalt-catalyzed intramolecular C-H amination reactions...

In comparison, intermolecular reaction met high challenges due to both enthalpy and entropy reasons. In 2007, He and coworkers developed a disilver-based new catalyst 11 which showed high efficiency for intramolecular C-H amination reaction (Scheme 10) [32]. Such an intermolecular C-H amination/amidation ran at mild condition. The new catalyst set has successfully been applied to intermolecular amination reaction for the first time (Scheme 11). In the reaction, the catalyst was added in two portions in order to increase the yield. Under typical reaction condition, AgOTf (2 mol%) and ligand (2.4 mol%) were mixed in DCM in a tube for 20 min. Then the substrate (5.0 or 10.0 eqmv.), PhI=NNs (1.0 equiv.) and 4 A molecular sieves (2 g/mmol) were added under N2 atmosphere. The tube was sealed and heated to 50°C for 2 h before another AgOTf (2 mol%) and ligand (2.4 mol%) mixed in DCM were added. The reaction was carried out at 50°C... 

Fiori KW, Espino CG, Brodsky BH, Du Bois J. A mechanistic analysis of the Rh-catalyzed intramolecular C-H amination reaction. Tetrahedron. 2009 65 3042-3051. 

The synthesis of indolines through an intramolecular C-H amination reaction has been reported (S cheme 3.65) [71 ]. The reaction was catalyzed by a common palladium compound and promoted by an iodme(lll) reagent. This catalyst system generated good to excellent yields of the heterocycles at 60 °C. 

Aryl azidoacrylates can be converted to the corresponding indoles by an iron(II) triflate-catalyzed intramolecular C-H amination reaction. A variety of electron-donating and electron-accepting groups is tolerated at the arene ring (Scheme 4-352). ... 

A recent DFT study has shown that retention of configuration observed for the above reactions is in agreement with the insertion of singlet nitrene and a concerted product formation [150 is the transition state for the reaction shown in Equation (6.135)]. Du Bois and coworkers have performed detailed mechanistic investigations of the intramolecular sulfamate ester C-H amination reaction catalyzed by a dirhodium complex. Reactivity patterns, Hammett analysis, and kinetic isotope effect studies have provided support for the concerted, asynchronous transition structure 151. A similar conclusion was arrived at for an analogous intermolecular process. ... 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

Another intramolecular synthesis of carbazoles 270 employed amino biaryls 269 as the starting materials with 2-picolinic acid as a directing group to facilitate a net C—H amination reaction under copper catalysis in the presence of Mn02 and acetic acid. The directing group is removed spontaneously after the initial amination (140L2892). 

There are numerous advantages to this approach in addition to avoiding complex purification procedures. For instance, it is now possible to further diversify the nitrogen substituent of the reagent, which has a profound impact on the practicality of C—H amination. In 2001, Du Bois and Espino first reported the intramolecular C—H insertion reaction with carbamates and diacetoxyiodobenzene in the presence of rhodium (II) acetate or rhodium (II) triphenylacetate dimer and magnesium oxide [33]. The corresponding oxazolidinone was isolated in high yields (Eq. (5.4)). 

Further evidence to exclude the triplet radical pathway includes the use of cyclopropyl substrates, which serve as a radical clock. In all cases, the reaction proceeds with no indication of ring fragmentation. The nature of the transition state of the C—H insertion step has been analyzed, via a Hammett study of the intermo-lecular C—H amination with p-substituted benzenes. A negative q value of 0.73 is obtained for the intermolecular reaction with trichloroethylsulfamate [71]. Such data indicate that there is a small, but significant, preference for electron-rich substrates, thus the resonance does contribute to the stabilization of a partial positive charge at the insertion carbon in the transition state. A kinetic isotope value of 1.9 is observed for competitive intramolecular C—H amination with a deuterated substrate (Eq. (5.21)). 

The mechanisms and enantioselectivities of the Rh2L4 (L = formate, Al-methyl form-amide, S-nap)-catalysed intramolecular C-H aminations of 3-phenylpropylsulfamate ester have been studied with BPW91 DFT computations. The Rh2(II,II)-catalysed reactions start with the oxidation of the Rh2(n,n) dimer to a triplet mixed-valent Rh2(II,ni)-nitrene radical, which facilitates radical H-atom abstraction. However, a direct C-H bond insertion is postulated for the Rh2(HCOO)4-catalysed reaction. The Rh2(Al-methylformamide)4-catalysed reaction is a two-step process and so is the mechanism of the Rh2(5-nap)4 (41)-catalysed reaction of 3-phenylpropylsulfamate ester. The mechanistic proposal is supported by the calculated 94.2% ee which is in good agreement with the observed 92% ee ... 

Cheng et al. developed an efficient [CuI(bpy)]2/02-catalyzed intramolecular oxidative C-H amination reaction of 2-aminoacetophenones for the synthesis of various AT-alkyl- or aryl-substituted isatins in moderate to good yields (Scheme 8.38). The 2-aminoglyoxal intermediate may be formed from 2-aminoaryl methyl ketone under oxidation conditions, and it could undergo intramolecular cyclization to give the desired isatins [76]. 

Scheme 8.38 [CuKbpyjJj/Oj-catalyzed intramolecular oxidative C-H amination reaction of 2-aminoacetophenones.

The copper-catalyzed synthesis of carbazoles from 2-aminobiphenyls via intramolecular C-H amination also could be realized using Mn02 as terminal oxidant (Scheme 8.42). The picolinamide-based bidentate directing group which could be spontaneously removed after the coupling reaction was crucial for this reaction. This Cu(OAc)2 catalytic system could proceed smoothly under I(III)-free conditions. Moreover, a few of heteroatom-containing carbazole core r-systems could be contained easily under the mild Cu(0Ac)2/Mn02 catalytic conditions [80]. 

The use of silver salts as catalysts for the direct C-H amination has been rarely reported. In 2004, the He group first reported a silver-catalyzed intramolecular cyclization of alkyl C(sp )-H bonds with the free N-H bonds, which is stereospecific and practical for constructing amine-containing organic molecules (Scheme 9.30) [36]. Within this C-H amination reaction, [Ag( Bu3tpy)2N03]+intermediate was detected by electrospray mass spectrometry. 

C-H alkylation and amination reactions involving metal-carbenoid and metal-nitrenoid species have been developed for many years, most extensively with (chiral) dirhodium(ll) carboxylate and carboxamidate complexes as catalysts [45]. When performed in intramolecular settings, such reactions offer versatile methods for the (enantioselective) synthesis of hetero- and carbocy-cles. In the past decade, Zhang and coworkers had explored the catalysis of cobalt(II)-porphyrin complexes for carbene- and nitrene-transfer reactions [46] and revealed a radical nature of such processes as a distinct mechanistic feature compared with typical metal (e.g., rhodium)-catalyzed carbenoid and nitrenoid reactions [47]. Described below are examples of heterocycle synthesis via cobalt(II)-porphyrin-catalyzed intramolecular C-H amination or C-H alkylation. 

As shown in the previous two sections, rhodium(n) dimers are superior catalysts for metal carbene C-H insertion reactions. For nitrene C-H insertion reactions, many catalysts found to be effective for carbene transfer are also effective for these reactions. Particularly, Rh2(OAc)4 has demonstrated great effectiveness in the inter- and intramolecular nitrene C-H insertions. The exploration of enantioselective C-H amination using chiral rhodium catalysts has been reported by several groups.225,244,253-255 Hashimoto s dirhodium tetrakis[A-tetrachlorophthaloyl-(A)-/ r/-leuci-nate], Rh2(derived rhodium complex, Rh2(i -BNP)4 48,244 afforded moderate enantiomeric excess for amidation of benzylic C-H bonds with NsN=IPh. 

Preliminary efforts to examine the mechanism of C-H amination proved inconclusive with respect to the intermediacy of carbamoyl iminoiodinane 12. Control experiments in which carbamate 11 and PhI(OAc)2 were heated in CD2CI2 at 40°C with and without MgO gave no indication of a reaction between substrate and oxidant by NMR. In Hne with these observations, synthesis of a carbamate-derived iodinane has remained elusive. The inability to prepare iminoiodinane reagents from carbamate esters precluded their evaluation in catalytic nitrene transfer chemistry. By employing the PhI(OAc)2/MgO conditions, however, 1° carbamates can now serve as effective N-atom sources. The synthetic scope of metal-catalyzed C-H amination processes is thus expanded considerably as a result of this invention. Details of the reaction mechanism for this rhodium-mediated intramolecular oxidation are presented in Section 17.8. 

A plausible mechanism for the one-pot synthesis ofcarbazoles is shown in Scheme 5. It consists of two interlinked catalytic cycles. In the first cycle a classical Buchwald-Hartwig amination reaction occurs to generate an intermediate 5 which then enters the second cycle by oxidative addition to Pd(0). The resulting Pd(II) complex then undergoes intramolecular C-H activation to give a six-membered palladacycle which subsequently yields the carbazole by reductive elimination. 

A novel synthesis of benzosultam 164 involves a Co-based catalytic system for intramolecular C-H animation with azides <07OL4889>. The commercially available cobalt tetraphenylporphyrin complex, Co(TPP) 163, is an effective catalyst for catalyzing C-H animation with arylsulfonyl azides 162 leading to benzosultams 164 in excellent yields. In addition to benzylic C-H bond, non-benzylic C-H bonds can also be intramolecularly aminated. For example, reaction of arylsulfonyl azides 165 with Co catalyst 163 results in a mixture of 5- and 6-membered ring products, 166 and 167. 

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